Asymmetric synthesis and the resolution of racemates constitute the methods for industrial preparation of pure enantiomers. Methods for such resolution include: direct preferential crystallization, crystallization of the diastereomeric salts, and kinetic resolution.
Also referred to as resolution by entrainment, preferential crystallization is economically more attractive because resolution is achieved without using any expensive optically active substance. Hence, this method is widely used on an industrial scale, for example, in the manufacture of .alpha.-methyl-L-dopa and chloramphenicol. See Enantiomers, Racemates, and Resolutions, Jacques, J.; Collet, A.; Wilen, S.H., J. Wiley & Sons, New York, 1981; Jacques, J.; Leclercq, M.; Brienne, M.J., Tetrahedron, 1981, 37, 1727-1733; and U.S. Pat. No. 4,865,770. It is technically feasible only with racemates which are so-called conglomerates and consist of mechanical mixtures of crystals of the two enantiomers. Unfortunately, only less than 20% of all racemates are conglomerates. The rest are true racemic compounds which cannot be separated by preferential crystallization (i.e., by seeding a supersaturated solution of racemic mixture with the crystals of one enantiomer). A conglomerate exhibits a minimum melting point for the racemic mixture while a racemic compound generally shows a maximum melting point. The success of preferential crystallization depends on the fact that the solubility of pure enantiomer is less than the solubility of the racemic mixture.